In 2005, Dr. Small and his colleagues showed that retromer is deficient in the brains of patients with Alzheimer’s disease. In cultured neurons, they showed that reducing retromer levels raised amyloid-beta levels, while increasing retromer levels had the opposite effect. Three years later, he showed that reducing retromer had the same effect in animal models, and that these changes led to Alzheimer's-like symptoms. Retromer abnormalities have also been observed in Parkinson’s disease.
In discussions at a scientific meeting, Dr. Small and co-senior authors Gregory A. Petsko, DPhil, Arthur J. Mahon Professor of Neurology and Neuroscience in the Feil Family Brain and Mind Research Institute and Director of the Helen and Robert Appel Alzheimer’s Disease Research Institute at Weill Cornell Medical College, and Dagmar Ringe, PhD, Harold and Bernice Davis Professor in the Departments of Biochemistry and Chemistry and in the Rosenstiel Basic Medical Sciences Research Center at Brandeis University, began wondering if there was a way to stabilize retromer (that is, prevent it from degrading) and bolster its function. “The idea that it would be beneficial to protect a protein’s structure is one that nature figured out a long time ago,” said Dr. Petsko. “We’re just learning how to do that pharmacologically.”
Other researchers had already determined retromer’s three-dimensional structure. “Our challenge was to find small molecules—or pharmacologic chaperones—that could bind to retromer’s weak point and stabilize the whole protein complex,” said Dr. Ringe.
This was accomplished through computerized virtual, or in silico, screening of known chemical compounds, simulating how the compounds might dock with the retromer protein complex. (In conventional screening, compounds are physically tested to see whether they interact with the intended target, a costlier and lengthier process.) The screening identified 100 potential retromer-stabilizing candidates, 24 of which showed particular promise. Of those, one compound, called R55, was found to significantly increase the stability of retromer when the complex was subjected to heat stress.
The researchers then looked at how R55 affected neurons of the hippocampus, a key brain structure involved in learning and memory. “One concern was that this compound would be toxic,” said Dr. Diego Berman, assistant professor of clinical pathology and cell biology at CUMC and a lead author. “But R55 was found to be relatively non-toxic in mouse neurons in cell culture.”
More important, a subsequent experiment showed that the compound significantly increased retromer levels and decreased amyloid-beta levels in cultured neurons taken from healthy mice and from a mouse model of Alzheimer's. The researchers are currently testing the clinical effects of R55 in the actual mouse model .
“The odds that this particular compound will pan out are low, but the paper provides a proof of principle for the efficacy of retromer pharmacologic chaperones,” said Dr. Petsko. “While we’re testing R55, we will be developing chemical analogs in the hope of finding compounds that are more effective.”
'Chaperone' compounds offer new approach to Alzheimer's treatment
April 20, 2014
Columbia University Medical Center
Researchers have identified a new class of compounds -- pharmacologic chaperones -- that can stabilize the retromer protein complex (the blue ...
Credit: Nature Chemical Biology and lab of Scott A. Small, MD/Columbia University Medical Center
A team of researchers from Columbia University Medical Center (CUMC), Weill Cornell Medical College, and Brandeis University has devised a wholly new approach to the treatment of Alzheimer's disease involving the so-called retromer protein complex. Retromer plays a vital role in neurons, steering amyloid precursor protein (APP) away from a region of the cell where APP is cleaved, creating the potentially toxic byproduct amyloid-beta, which is thought to contribute to the development of Alzheimer's.
Using computer-based virtual screening, the researchers identified a new class of compounds, called pharmacologic chaperones, that can significantly increase retromer levels and decrease amyloid-beta levels in cultured hippocampal neurons, without apparent cell toxicity. The study was published today in the online edition of the journal Nature Chemical Biology.
“Our findings identify a novel class of pharmacologic agents that are designed to treat neurologic disease by targeting a defect in cell biology, rather than a defect in molecular biology,” said Scott Small, MD, the Boris and Rose Katz Professor of Neurology, Director of the Alzheimer's Disease Research Center in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain at CUMC, and a senior author of the paper. “This approach may prove to be safer and more effective than conventional treatments for neurologic disease, which typically target single proteins.”
In 2005, Dr. Small and his colleagues showed that retromer is deficient in the brains of patients with Alzheimer’s disease. In cultured neurons, they showed that
I think there is still a promising future for Prana's science, and see this as a temporary setback.
“Before success comes in any man’s life, he is sure to meet with much temporary defeat, and, perhaps, some failure. When defeat overtakes a man, the easiest and most logical thing to do is to quit. That is exactly what the majority of men do. More than five hundred of the most successful men this country has ever known told the author their greatest success came just one step beyond the point at which defeat had overtaken them.”
― Napoleon Hill, Think and Grow Rich
And to quote Donald Fagan
Standing tough under stars and stripes
We can tell
This dream's in sight
You've got to admit it
At this point in time that it's clear
The future looks bright
On that train all graphite and glitter
Undersea by rail
Ninety minutes from new york to paris
Well by seventy-six we'll be a.o.k.
What a beautiful world this will be
What a glorious time to be free. Less
Thanks Pivalde, That would a huge market for PBT2. Once the rest of the science community realizes how important the balance of these trace metals are, Pranas valuation will go much higher in my opninion. As Rudy said in a recent interview they are very few others companies in this field.
Tom, I have been a long of Prana for may years and want to thank you for sharing your experience. The longs on this board are investors with a lot of compassion towards those afflicted by AD. This is also true of Pran's scientists and management . As is have stated before that is capitalism at its best my friends.
Dr Neil Telling from the University of Keele, who lead the research in collaboration with colleagues at the University of Warwick and the University of Florida, commented: "Alzheimer's is a sensitive and emotive area of research. The disease involves progressive brain cell failure, the reasons for which are still not fully understood. When findings showed increased levels of toxic iron within Alzheimer's disease tissues, we realised that techniques we had used to study other iron based materials could be applied to understand where this toxic iron came from. Our observations suggest an origin for the toxic iron; that it may well be made toxic by the lesions themselves. This could open up new avenues of research into treatments to stop the build-up of this neurotoxic substance, potentially limiting the damage done by Alzheimer's. Understanding how this toxic iron forms could also tell us where to look for early stages of the disease in MRI scans, perhaps even before irreversible brain damage occurs. It's at an early stage but these promising results seem to be another piece of the jigsaw to fully understand Alzheimer's."
Yes I recommend everyone read this major new paper google below.Ferrous iron formation following the co-aggregation of ferric iron and the Alzheimer's disease peptide β-amyloid (1–42)
J. Everett1, E. Céspedes1, L. R. Shelford2, C. Exley3, J. F. Collingwood4, J. Dobson5,6, G. van der Laan7, C. A. Jenkins8, E. Arenholz8 and N. D. Telling1⇑
+ Author Affiliations
More information: The full research paper "Ferrous iron formation following the co-aggregation of ferric iron and the Alzheimer's disease peptide β-amyloid (1-42)" was published in Journal of the Royal Society Interface on Wednesday, 26th March 2014 DOI: 10.1098/rsif.2014.0165.
A related paper was published recently online by the same research team in the journal ACS Inorganic Chemistry entitled "Evidence of Redox-Active Iron Formation Following Aggregation of Ferrihydrite and the Alzheimer's Disease Peptide β‑Amyloid" DOI: 10.1021/ic402406g.
Journal reference: Journal of the Royal Society Interface Inorganic Chemistry
In a paper published today, British scientists have found evidence that biological material contributing to lesions in the brain, characteristic in Alzheimer's patients, may also cause the build-up of brain-cell-damaging toxic iron. Scientists have made the discovery using advanced imaging techniques at giant X-ray facilities - the Diamond Light Source synchrotron in Oxfordshire and other synchrotrons in Switzerland and the US.Iron occurs naturally in the human body, including the brain. The conversion of this iron between two chemical forms is essential for normal function. However, one of these forms of iron, known as ferrous iron, can be highly toxic if it is overproduced or builds up in tissues where it can't be processed and removed properly. Scientists have known for some time that this toxic iron builds up in the same location as the brain lesions caused by Alzheimer's disease.
Researchers have been studying the protein fragment that makes up the Alzheimer's lesions, a peptide known as beta-amyloid, to try to understand how and why the build-up of toxic iron is occurring; and whether it's a cause or a symptom of the brain cell damage in Alzheimer's patients.
At the UK's national synchrotron, Diamond Light Source, beams of light 10 billion times brighter than the sun, were used to shine a light on the problem, to study the chemical and magnetic makeup of the iron after it had interacted with the beta-amyloid peptide. By using these techniques along with electron microscopy they witnessed predominant biological form of iron changing into the more toxic ferrous form. As well as Diamond Light Source, studies were also carried out at the Swiss Light Source and the Advanced Light Source in the USA, using applied advanced x-ray techniques, more commonly used to study the latest hi-tech materials.
The experiments revealed that the peptide that makes up Alzheimer's lesions is capable of converting iron into the form which could be causing damage to brain cells. This means that the lesions caused by Alzheimer's could be causing a subtle disruption in how the brain manages iron, confronting brain cells with a level of toxicity that they simply cannot manage.
This discovery paves the way for future medical research into treatments that could halt or manage the conversion of iron into this toxic form, potentially slowing or limiting the damage to the brain. It could also lead to developments in using magnetic resonance imaging (MRI) to detect early stages of the disease by mapping altered patterns of iron in the brain.